The disclosure relates to using perfused human-derived organs and/or tissues, such as glandular organs and/or tissues, to evaluate hormone, or other bodily chemical, disruption caused by substances. Methods of the invention permit assessment of such substances using human organs and/or tissues, particularly organs unsuitable for transplantation, on an organ-by-organ or tissue-by-tissue basis.
Methodologies available for assessing properties, fates and effects of substances in humans span many levels of mammalian organization from in vivo studies to studies of isolated organs or tissues, tissue slices, cultured cell types, subcellular particles, multi-enzyme complexes and molecular interactions. In practice, these complex methods often result in considerable wasted time, effort and resources in many fields where substances may undergo several rounds of testing only to find that later testing or market experience reveals undesirable effects in humans, often with tragic consequences.
Historically, attempts to weed-out substances having an unacceptable benefit/risk ratio have relied on in vivo non-human animal studies using several species, such as rodent species. Limitations of toxicity studies in non-human species have long been, and still are, well recognized, but short of performing toxicity studies in humans in vivo there has been no viable alternative. Attempts have been made to bridge the gap between non-human testing and human effects using tissue preparations including subcellular particles, e.g., microsomes, primary cells and cells in culture, e.g., hepatocytes, and tissue slices. Although these in vitro tissue preparations generate much useful data, the farther the tissue preparation is from the whole organism, the greater the risk of false positives and false negatives. For example, false positives or false negatives may occur when assessing whether test substances are toxic when administered alone or with other co-administered substances. Moreover, there is no guarantee that pharmacokinetic/toxicity relationships in normal human tissues determined in vitro will be the same as in normal or diseased human tissues in vivo.
As it is not ethical to use humans for exploratory toxicity testing, the choice has been to perform in vivo testing on a variety of non-human animal species and/or in vitro testing using human biological samples. For example, drug testing using ex vivo human organs has been disclosed in the present assignee's published PCT Application No. WO 2005/074681 and U.S. patent application Ser. No. 10/768,167 (the entire contents of which are hereby incorporated by reference in their entirety), which notes that organs unsuitable for transplantation may be used for such testing.
Studies have shown that human reproductive health may be linked to environmental substances that have oestrogenic, androgenic or related potentials. A number of observations have been made from human epidemiological studies that include reduced sperm counts, reduced fertility, increased incidence of testicular cancer and congenital birth defects in men and increased incidence of breast cancer in women possibly due to environmental substances. In various wildlife species, the occurrence of gross birth deformities, behavioral abnormalities and feminization/masculinization have been reported. Clearly, many concerns exist that such substances may adversely affect human reproductive health and other aspects of human well-being. See, e.g., Draft Detailed Review Paper: Appraisal of Test Methods for Sex-Hormone Disrupting Chemicals, from the Series on Testing and Assessment, OECD Environmental Health and Safety Publications, Environment Directorate, Organisation for Economic Co-operation and Development, Paris, France (1997).